Induction of P-glycoprotein and Bcrp at the rat blood–brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation

Authors

  • Salah Yousif,

    1. CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
    2. INSERM, U705, Paris, France
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    • These authors contributed equally to this work.
  • Catarina Chaves,

    1. CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
    2. INSERM, U705, Paris, France
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    • These authors contributed equally to this work.
  • Sophie Potin,

    1. CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
    2. INSERM, U705, Paris, France
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  • Isabelle Margaill,

    1. EA 4475, Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
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  • Jean-Michel Scherrmann,

    1. CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
    2. INSERM, U705, Paris, France
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  • Xavier Declèves

    Corresponding author
    1. CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France
    2. INSERM, U705, Paris, France
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Abstract

Subchronic morphine treatment induces P-glycoprotein (P-gp) up-regulation at the blood–brain barrier. This study investigates the rate and extent to which P-gp and breast cancer-resistance protein (Bcrp) increase at the rat blood–brain barrier following subchronic morphine treatment. Rats were given increasing doses of morphine (10–40 mg/kg) or saline i.p. twice daily for 5 days. The brain cortex large vessels and microvessels were then mechanical isolated 6, 9, 12, 24, and 36 h after the last injection. The gene and protein expression of P-gp and Bcrp in morphine-treated and control rats were compared by qRT-PCR and western blotting. The levels of Mdr1a and Bcrp mRNAs were not significantly modified 6 h post morphine, but the Mdr1a mRNA increased 1.4-fold and Bcrp mRNA 2.4-fold at 24 h. P-gp and Bcrp protein expression in brain microvessels was unchanged 6 h post morphine and increased 1.5-fold at 24 h. This effect was more pronounced in large vessels than in microvessels. However, extracellular morphine concentrations of 0.01–10 μM did not modify the expressions of the MDR1 and BCRP genes in hCMEC/D3 human endothelial brain cells in vitro. MK-801 (NMDA antagonist) and meloxicam (cyclo-oxygenase-2 inhibitor) given after morphine treatment completely blocked P-gp and Bcrp up-regulation. Interestingly, misoprostol and iloprost, two well-known agonists of prostaglandin E2 receptors induced both MDR1 and BCRP mRNA levels in hCMEC/D3. Thus, morphine does not directly stimulate P-gp and Bcrp expression by the brain endothelium, but glutamate released during morphine withdrawal may do so by activating the NMDA/cyclo-oxygenase-2 cascade.

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